Piperazine → Tert-butyl 3-(2-(2-bromo-3-methylphenylamino)-2-oxoethyl)piperazine-1-carboxylate

HRID 80513Notes

Reaction equation

HRID 80513 reaction equation
C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]3[CH2:31][C:32]([OH:34])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.C(Cl)(=O)C(Cl)=O.[Br:41][C:42]1[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:43]=1[NH2:44].C(N(C(C)C)CC)(C)C.N1CCNCC1>ClCCl.CN(C)C=O.O1CCCC1>[Br:41][C:42]1[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:43]=1[NH:44][C:32](=[O:34])[CH2:31][CH:19]1[NH:18][CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20]1

Participants

9

Reactant 5

HCID 4837PiperazineHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 6037812-Bromo-3-methylanilineHCID 27567961-Fmoc-4-Boc-Piperazine-2-acetic acid

Product 1

HCID 67248813Tert-butyl 3-(2-(2-bromo-3-methylphenylamino)-2-oxoethyl)piperazine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (3.00 g, 6.43 mmol) in dichloromethane (50 mL) with N,N-dimethylformamide (2 drops) was added oxalyl chloride (1.13 mL, 12.9 mmol) drop wise. The reaction mixture was stirred at room temperature for 1 hour, and then it was concentrated. The concentrate is taken up in tetrahydrofuran (50 mL) and 2-bromo-3-methyl aniline (1.33 g, 7.07 mmol) was added in tetrahydrofuran (5 mL) and diisopropylethylamine (5.62 mL, 36.2 mmol). The solution is heated to 70° C. for 2 hours. The mixture was then cooled to 50° C. and piperazine (1.66 g, 19.3 mmol) was added. The reaction mixture stirred for 16 hours before concentration onto silica gel. Purification via flash chromatography (0-20% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.54-7.71 (m, 1H), 7.06-7.31 (m, 2H), 3.62-3.98 (m, 2H), 2.26-3.45 (m, 10H), 0.87-1.05 (m, 9H); MS (APCI+) m/z 412, 414 (M+H)+.

Workup

  1. concentrationit was concentrated
  2. temperatureThe solution is heated to 70° C. for 2 hours
  3. temperatureThe mixture was then cooled to 50° C.
  4. stirringThe reaction mixture stirred for 16 hours before concentration onto silica gel
  5. customPurification via flash chromatography (0-20% methanol/dichloromethane)

Sources & evidence

ORD record
ord-133e72aa28494d8fa58506e0abf7ead6
Source dataset
uspto-grants-2014_09
Patent number
US08846663B2

Reaction notes

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